Correction of dendritic cells defects in cancer

描述（由申请人提供）：尽管在临床试验中测试的免疫治疗策略具有很高的前景，但尚未为大多数患者带来切实的益处。许多临床试验已经证明成功地产生了针对肿瘤特异性抗原的免疫反应。然而，在大多数患者中，这些反应与临床反应并不相关。越来越清楚的是，限制免疫治疗有效性的主要因素之一是免疫抑制肿瘤微环境，它阻止细胞毒性T细胞（CTL）识别和消除肿瘤。本研究旨在了解骨髓源性抑制细胞（MDSC）诱导t细胞缺陷的机制。在实现项目目标的过程中，我们发现MDSC介导的t细胞耐受的主要机制之一是由MDSC增加活性氧（ROS）和氮（RNS）物种的产生引起的TCR的翻译后修饰。在目前的修订中，我们建议扩大父母补助金的范围。基于我们新的初步数据，我们提出过氧亚硝酸盐和其他ROS通过浸润骨髓细胞或肿瘤细胞在肿瘤微环境中产生的影响远不止对T细胞的影响。我们认为过氧亚硝酸盐和ROS引起肿瘤细胞上表达的MHC I类分子和/或这些MHC I类分子所呈现的肿瘤特异性肽的修饰。这将使ctl特异性的肿瘤抗原衍生肽不能识别和消除肿瘤细胞。因此，即使癌症免疫治疗导致产生有效的抗原特异性ctl，或者如果这些ctl是在体外产生的，然后过继性地转移到患者身上，MHC I类的翻译后修饰也会否定任何可能的抗肿瘤作用。由于骨髓细胞浸润和过氧亚硝酸盐产生水平因患者而异，这可能解释了患者采用过继性T细胞转移或疫苗治疗的不同结果。在提出的研究中，我们计划通过实验来验证这一假设。我们还将通过使用新型化合物RTA 402来测试逆转过氧亚硝酸盐影响的可能性，该化合物已被证明在阻断活性氧和减少过氧亚硝酸盐产生方面具有高水平的活性。我们提出以下具体目标：目的探讨肺癌动物模型中与活性氧和活性氮过量产生相关的肿瘤逃逸机制。具体目标2。在肺癌临床前模型中确定新型治疗化合物逆转过氧亚硝酸盐诱导的肿瘤从细胞毒性T细胞逃逸的能力。

DESCRIPTION (provided by applicant): Despite high promise the immunotherapeutic strategies that have been tested in clinical trials have not yet delivered tangible benefits to most patients. Numerous clinical trials have demonstrated successful generation of immune responses against tumor-specific antigens. However, these responses have not been associated with clinical responses in most patients. It has become increasingly clear that one of the major factors that limit the effectiveness of immunotherapy is the immunosuppressive tumor microenvironment, which prevents cytotoxic T cells (CTL) from recognizing and eliminating tumor. Parent grant is focused to understanding the mechanisms of T-cell defects induced by myeloid-derived suppressor cells (MDSC). In a course of implementation of the goals of the project we found that one of the major mechanisms of MDSC mediated T-cell tolerance was a posttranslational modification of TCR caused by increased production of reactive oxygen (ROS) and nitrogen (RNS) species by MDSC. In current revision we propose to expand the scope of the parent grant. Based on our new preliminary data we propose that effect of peroxynitrite and other ROS produced in tumor microenvironment by infiltrating myeloid cells or tumor cells is much broader than just effect on T cells. We suggest that peroxynitrite and ROS cause modification of MHC class I molecules expressed on tumor cells and/or tumor-specific peptides presented by those MHC class I molecules. This would make CTLs specific for tumor antigen derived peptides unable to recognize and eliminate tumor cells. Thus, even if cancer immunotherapy results in the generation of potent antigen-specific CTLs or if these CTLs are generated in vitro and then adoptively transferred to patients, post-translational modification of MHC class I would negate any possible antitumor effect. Since the level of myeloid cell infiltration and peroxynitrite production varies from patient to patient this may account for variable results of patients' treatment with adoptive transfer of T cells or vaccines. In the proposed study we plan to experimentally test this hypothesis. We will also test the possibility of reversing the effect of peroxynitrite by employing the novel compound RTA 402, which has been demonstrated to have a high level of activity in blocking reactive oxygen species and decreasing peroxynitrite production. We propose the following specific aims: Specific aim 1. To identify the mechanism of tumor escape associated with hyperproduction of reactive oxygen and nitrogen species in animal models of lung cancer. Specific aim 2. To determine in preclinical models of lung cancer the ability of novel therapeutic compounds to reverse the peroxynitrite-inducible tumor escape from cytotoxic T cells. PUBLIC HEALTH RELEVANCE: Proposed research will investigate novel mechanism of tumor escape associated with increased production of peroxynitrite in tumor tissues. We will test novel hypothesis that inability of cytotoxic T lymphocytes to recognize and eliminate tumor cells was caused in part by peroxynitrite inducible modifications of MHC class I and/or peptide epitopes on the surface of tumor cells. We will investigate the mechanism of this phenomenon and test several therapeutic approaches to eliminate this effect with goal to enhance the effect of cancer immunotherapy.